Citations

Abstract The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8+ T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-β signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis.

ABSTRACTIntracortical bone remodeling is persistent throughout life, leading to age related increases in osteon population density (OPD). Intracortical porosity also increases with age in many mammals including humans, contributing to bone fragility and fracture risk. Unbalanced bone resorption and formation during disuse (e.g., physical inactivity) also increases intracortical porosity. In contrast, hibernating bears are a naturally occurring model for the prevention of both age‐related and disuse osteoporoses. Intracortical bone remodeling is decreased during hibernation, but resorption and formation remain balanced. Black bears spend 0.25–7 months in hibernation annually depending on climate and food availability. We found longer hibernating bears demonstrate lower OPD and higher cortical bone mineralization than bears with shorter hibernation durations, but we surprisingly found longer hibernating bears had higher intracortical porosity. However, bears from three different latitudes showed age‐related decreases in intracortical porosity, indicating that regardless of hibernation duration, black bears do not show the disuse‐ or age‐related increases in intracortical porosity which is typical of other animals. This ability to prevent increases in intracortical porosity likely contributes to their ability to maintain bone strength during prolonged periods of physical inactivity and throughout life. Improving our understanding of the unique bone metabolism in hibernating bears will potentially increase our ability to develop treatments for age‐ and disuse‐related osteoporoses in humans. Anat Rec, 2013. © 2013 Wiley Periodicals, Inc.

Abstract Background and aims Affect balance reflects relative levels of negative affect (NA) and positive affect (PA) and includes four styles: Healthy (low NA/high PA), Depressive (high NA/low PA), Reactive (high NA/high PA) and Low (low NA/low PA). These affect balance styles may have important associations with clinical outcomes in patients with fibromyalgia. Herein, we evaluated the severity of core fibromyalgia symptom domains as described by the Outcomes Research in Rheumatology-Fibromyalgia working group in the context of the four affect balance styles. Methods Data from 735 patients with fibromyalgia who completed the Brief Pain Inventory, Multidimensional Fatigue Inventory, Profile of Mood States, Medical Outcomes Sleep Scale, Multiple Ability Self-Report Questionnaire, Fibromyalgia Impact Questionnaire-Revised, Medical Outcomes Study Short Form-36, and Positive and Negative Affect Schedule were included in this analysis. Results The majority (51.8%) of patients in our sample had a Depressive affect balance style; compared to patients with a Healthy affect balance style, they scored significantly worse in all fibromyalgia symptom domains including pain, fatigue, sleep disturbance, dyscognition, depression, anxiety, stiffness, and functional status ( P = <.001 to .004). Overall, patients with a Healthy affect balance style had the lowest level of symptoms, while symptom levels of those with Reactive and Low affect balance styles were distributed in between those of the Depressive and Healthy groups. Conclusions and implications The results of our cross-sectional study suggest that having a Healthy affect balance style is associated with better physical and psychological symptom profiles in fibromyalgia. Futures studies evaluating these associations longitudinally could provide rationale for evaluating the effect of psychological interventions on affect balance and clinical outcomes in fibromyalgia.